Girondalones

ABSTRACT

Girondalones of the formula I useful as microbicides ##STR1## wherein A is a residue of a dialdehyde; 
     R 1  is independently selected from the group consisting of R 2  and (C 1  -C 18 )alkyl and; 
     R 2  is ##STR2## wherein (i) X 1  and X 2  can be joined to form a 5 or 6 membered fused carbocyclic ring, said ring being saturated, unsaturated, or aromatic; or 
     (ii) X 1  =Cl, H, methyl, or Br; and 
      X 2  =H, Cl, or Br.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the field of antimicrobial compounds and compositions. In particular, it relates to new isothiazolyl compounds which are usefull as microbicides and are referred to as girondalones.

2. Description of the Prior Art

Lewis et al., U.S. Pat. Nos. 3,761,488; 3,544,580; 3,835,150; 3,706,757; and 4,105,431, all assigned to Rohm and Haas Co., the same assignee as the present invention, disclose 3-isothiazolone compounds. Willingham et al. in U.S. Ser. Nos. 438,816, filed Nov. 17, 1989 and 601,964, filed Oct. 22, 1990, both assigned to Rohm and Haas Company, disclose stabilizing said isothiazolone compounds with carbonyl compounds. Other stabilization methods for isothiazolones are disclosed in a series of patents assigned to the same assignee.

It has been a problem in the art to find an ideal stabilization method for the 3-isothiazolone compounds which are outstanding anti-microbial compounds but are chemically and thermally unstable unless one of the aforementioned stabilization systems is used. Another problem with the 3-isothiazolones is that they can be skin sensitizers under certain conditions.

SUMMARY OF THE INVENTION

It was an object of the present invention to provide a new stabilization method for 3-isothiazolone compounds which improved upon prior methods. It was another object to provide a way to decrease the skin sensitization potential of the 3-isothiazolones. In seeking to achieve these objectives, a new class of compounds was unexpectedly discovered which not only achieves these objectives, but have additional advantages in their own right.

These objects and others which will become apparent from the following disclosure are achieved by the present invention which in one aspect comprises girondalone compounds of the formula ##STR3## wherein A is a residue of a dialdehyde; of the formula OHC--A--CHO

R₁ is independently selected from the group consisting of R₂ and (C₁ -C₁₈)alkyl and;

R₂ is ##STR4## wherein (i) X₁ and X₂ can be joined to form a 5 or 6 membered fused carbocyclic ring, said ring being saturated, unsaturated, or aromatic; or

(ii) X₁ =Cl, H, methyl, or Br; and

X₂ =H, Cl, or Br.

In another aspect the invention comprises preparing a girondalone compound of formula I by a method comprising reacting a compound of the formula ##STR5## wherein R₃ is (C₁ -C₁₈)alkyl, with 3-hydroxyisothiazole or a substituted derivative thereof of the formula ##STR6##

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

The preferred method of preparing the girondalone compounds of the invention is as set forth in the Summary. It is preferred to conduct the reaction by using heat and in the presence of a weak acid such as propionic acid. The product is preferably a mixture of compounds of formula I with some compounds having no R₁ =R₂, some having one R₁ =R₂, and some having two or three R₁ =R₂.

Examples of suitable dialdehydes represented by A are glutaraldehyde; malonaldehyde; succinaldehyde; octanedial; 2,2-sulfonyl-bis-acetaldehyde; 2,2-oxy-bis-acetaldehyde; 2,2-alkylphosphine oxide-bis-acetaldehyde; succinic acid-2,3-bis-acetaldehyde; phthaldehyde; homophthalaldehyde; 4-octenedial; 2-cylopentene-1;4-dial, and glyoxal. A special case is when A represents the residue of glyoxal in which case the girondalone compounds of formula (I) can be represented by formula (V) as follows: ##STR7##

The girondalone compounds of the invention are especially active and efficient antimicrobial compounds. Among the preferred compounds of formula are the following:

1.) 1,3,3-Trimethoxy-1-(5-chloro-isothiazoloxy-3yl) propane;

2.) 1,3-Dimethoxy-1,3-bis-(5-chloro-isothiazoloxy-3-yl) propane;

3.) 1,3,3-Trimethoxy-l-(isothiazoloxy-3-yl) propane; and

4.) 1,3-Dimethoxy-1,3-bis-(isothiazoloxy-3-yl) propane

The melting point of compound 2 was 57° C. Compounds 1, 3 and 4 were oils.

The following lists specific industries and applications of the girondalone compounds and compositions.

    ______________________________________                                         Industry        Application                                                    ______________________________________                                         Adhesives, sealants                                                                            adhesives                                                                      caulks                                                                         sealants                                                       Agriculture/food chain                                                                         adjuvant preservation                                                          agricultural active ingredient                                                 agricultural chemical                                                          preservative                                                                   agricultural formulations                                                      preservation                                                                   animal feed preservation                                                       dairy chemicals                                                                fertilizer preservation                                                        food preservation                                                              food processing chemicals                                                      grain preservation                                                             post-harvest produce protection                                                sugar processing                                                               tobacco                                                        Construction products                                                                          asphalt / concrete                                                             cement modifiers                                                               construction products                                                          roof mastics                                                                   synthetic stucco                                                               wall mastics                                                                   joint cement                                                   Cosmetics and toiletries                                                                       cosmetics                                                                      raw materials for cosmetics,                                                   toiletries                                                                     toiletries                                                     Disinfectants, antiseptics                                                                     antiseptic                                                                     disinfectant                                                   Emulsions, dispersions                                                                         aqueous dispersions                                                            dispersed pigments                                                             latex                                                                          photographic emulsions                                                         pigment slurries                                                               polymer latices                                                Formulated consumer &                                                                          air fresheners                                                 industrial products                                                                            fabric softeners                                                               hand cleaners                                                                  polishes, floor, furniture, shoe                                               sponges & towelettes                                                           spray strach                                                                   waxes                                                          Industrial processing, misc                                                                    dry cleaning fluids preservation                                               electrodeposition paint, baths,                                                rinses                                                                         electrodeposition pretreatment,                                                post rinses                                                                    industrial fluids preservation                                                 pasteurization baths                                                           process aid preservation                                       Industrial water treatment                                                                     air washers                                                                    cooling towers                                                                 cooling water                                                                  water cooling                                                  Laundry         household laundry products                                                     laundered goods                                                                laundry rinse water                                                            pre-washers                                                                    sanitizers-laundry                                                             removers, spot & stain                                         Leather, leather products                                                                      leather and hide                                                               leather and hide products                                      Lubricants, hydraulic aids                                                                     automotive lubricants and                                                      fluids                                                                         conveyor lubricants                                                            greases                                                                        hydraulic fluids                                                               hydraulic oils                                                                 lubricants                                                     Medical devices diagnostic enzymes                                                             diagnostic kits                                                                medical devices                                                Metalworking & related app's                                                                   cutting fluids                                                                 metal cleaning                                                                 metalworking fluids                                            Odor control    air conditioning                                               (active ingredient)                                                                            animal bedding                                                                 cat litter                                                                     chemical toilet prep'ns                                                        deodorizers                                                                    humidifiers                                                                    industrial deodorants                                                          sanitary formulations                                                          toilet bowls                                                   Paints and coatings                                                                            coating emulsions                                                              paints                                                         Paper and wood pulp, their                                                                     absorbant materials of paper                                   products        and wood pulp                                                                  packaging materials of paper                                                   and wood pulp                                                                  paper                                                                          paper products                                                                 paper treatment                                                                soap wrap                                                                      wood pulp                                                                      wood pulp products                                             Paper mill      paper mill slimicides                                                          pulp and paper slurries                                        Petroleum refining, fuels                                                                      aviation fuels (jet fuel,                                      aviation        gas)                                                                           burner, diesel and turbine fuel                                                oils                                                                           coal slurries                                                                  diesel fuel additives                                                          diesel fuels                                                                   fuels                                                                          gasoline                                                                       heating oils                                                                   hydrocarbons                                                                   kerosene                                                                       liquefied petroleum gas                                                        petrochemical feedstocks                                                       petroleum products, storage,                                                   transportation and production                                                  recycled petroleum products                                                    residual fuel oils                                                             turbine oils                                                   Photographic chemicals and                                                                     photographic processing - wash                                 process         water, rinses                                                                  photoplate processing chemicals                                                (developers, stabilizers etc)                                  Printing        fountain solutions (printing)                                                  ink components (pigments,                                                      resins, solvents, etc)                                                         inks                                                           Sanitizers (active)                                                                            sanitizers                                                                     sanitizers-dairy                                                               sanitizers-dental                                                              sanitizers-fermentation                                                        sanitizers-food preparation                                                    sanitizers-food processing                                                     sanitizers-medical                                                             sanitizers-rendering                                                           sanitizers-veterinary                                          Soaps, detergents, cleaners                                                                    cleaners                                                                       detergents, hand automatic                                                     laundry, other                                                                 household cleaners                                                             industrial cleaners                                                            liquid soaps, hand, dish,                                                      laundry                                                                        oil and grease remover                                                         powdered soaps                                                                 raw materials for cleaning                                                     products                                                                       soaps                                                                          surfactants                                                    Textiles, textile products                                                                     bonded fabrics                                                                 burlap                                                                         canvas                                                                         canvas goods                                                                   carpet backing                                                                 carpets                                                                        clothing                                                                       coated fabrics                                                                 curtains                                                                       draperies                                                                      engineering textiles                                                           fibers                                                                         geotextiles                                                                    goods made of textiles                                                         knitted fabrics                                                                nets                                                                           nonwoven fabrics                                                               rope                                                                           rugs                                                                           textile accessories                                                            textile products                                                               textiles                                                                       upholstery                                                                     woven fabrics                                                                  yarn                                                           Textile processing                                                                             dye fixatives                                                                  dyes                                                                           fiber lubricants                                                               hand modifiers                                                                 sizes                                                                          textile processing fluids                                      Therapeutic (active or                                                                         animal health/veterinary                                       preservative)   aquaculture                                                                    dental                                                                         human health                                                                   pharmaceutical /therapeutic                                    Water purification                                                                             charcoal beds                                                                  deionization resins                                                            filters                                                                        membranes                                                                      reverse osmosis membranes                                                      ultrafilters                                                                   water purification                                                             water purification pipes, tubing                               Wood applications                                                                              lazures (wood stains)                                                          wood                                                                           wood products                                                  Miscellaneous   alcohols                                                                       bedding incorporating water or                                                 gels                                                                           ceramic                                                                        contact lens cases-leaching                                                    electronic circuitry                                                           electronics chemicals                                                          enzymes-food production                                                        enzymes-industrial                                                             gel cushions                                                                   laboratory reagents                                                            marine antifoulants                                                            mildewcides                                                                    mining applications                                                            natural rubber latex                                                           oil field applications                                                         pipes                                                                          plastics                                                                       polymer systems                                                                polymers and resins (synthetic                                                 and natural)                                                                   reagent preservation                                                           rubber                                                                         rubber products                                                                skin remover                                                                   solid protective/decorative                                                    films                                                                          swimming pools                                                                 waste treatment                                                                water beds                                                     ______________________________________                                    

The amounts of the girondalone compound to be used depend on the application. The useful amounts for a particular application are similar to amounts used for other microbicidal compounds.

The girondalone compound can be used in combination with other microbicides. The term "microbicide" is considered equivalent to "antimicrobial" as used herein.

Suitable methods of application of girondalone compounds of formula I to control fungi, bacteria, algae, viruses, yeasts, and the like are in amounts and with carriers, etc., as are well known in the art.

The following examples are presented to illustrate a few embodiments of the invention, but are not to be considered as limiting.

EXAMPLE 1 1,3,3-Trimethoxy-1-(isothiazoloxy-3-yl) Propane and 1,3-Dimethoxy-1,3bis-(isothiazoloxy,3-yl) Propane

To a stirred mixture of 3-hydroxy-isothiazole (6 g, 0.0594 m) and malonaldehyde bis(dimethyl acetal)(8.24g., 0.0502m), propionic acid (0.2 g., 0.0027 m) was added.

The mixture was heated at 100 ° C. with stirring for 14 hours, cooled, and poured into saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The ethyl acetate portion was washed with water, dried (MgSO₄), and concentrated to give a mixture of 1,3,3-trimethoxy-1-(isothiazoloxy-3-yl) propane and 1,3-dimethoxy-1,3-bis-(isothiazoloxy-3-yl) propane as an oil.

The girondalone compounds were separated by column chromatography on silica gel by first eluting with ethyl acetate to give 2.7 g 1,3,3-trimethoxy-1-(isothiazoloxy-3-yl) propane followed by methanol to elute 1,3-dimethoxy-1,3-bis-(isothiazoloxy-3-yl) propane (2.5 g.).

NMR (d₆ -acetone) 8.6(1H), 6.2(1H), 5.7(1H), 4.5(1H), 3.3(9H), 2.0(m, 2H) 8.7(2H), 6.3(2H), 5.7(1H), 5.4(1H), 3.3(6H), 2.0-2.7(m,2H).

EXAMPLE 2 1,3,3-Trimethoxy-1-(5-chloro-isothiazoloxy-3-yl) Propane and 1,3-Dimethoxy-1,3-bis-(5-chloro-isothiazoloxy-3-yl) Propane

To a stirred mixture of 5-chloro-3-hydroxy-isothiazole (2 g., 0.0148 m) and malonaldehyde bis (dimethyl acetal) (3.42 g., 0.0209 m), propionic acid (0.12 g., 0.0020m) was added. The mixture was heated at 100 ° C. with stirring for 12 hours, then cooled and poured into saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The ethyl acetate portion was washed with water, dried (MgSO₄), and concentrated. The girondalone products were separated by column chromatography using ethyl acetate:hexane(1:1) as eluant to yield 0.44 g. of 1,3,3-trimethoxy-1-(5-chloro-isothiazoloxy-3-yl)propane as an oil and 0.80 g. of 1,3-dimethoxy-1,3-bis-(5-chloro-isothiazoloxy-3-yl) propane as a solid; mp 57° C.

NMR (d₃ -chloroform) 6.3(1H), 5.8(1H), 4.6(1H), 3.4(9H), 2.1 (m,2H) 7.4(1H), 6.4(1H), 5.9(1H), 5.7(1H), 3.5(6H), 2.4 (m,2H).

EXAMPLE 3 Biological Activity

Efficacy against bacteria and fungi was carried out. A minimum inhibitory concentration (MIC) value was obtained using Trypticase Soy Broth, pH 7.0 and preparing a serial dilution with a starting concentration of 500 ppm. A stock solution of the test compound was made in dimethyl sulfoxide/acetone/water mixture. The test organisms used to demonstrate biocidal activity are listed in Table 1. The MIC's of the compounds of this invention against the test organisms are shown in Table 2. The tests were repeated with the media being adjusted to pH 5, 7, and 8.5. The results are shown in Tables 3 and 4. The following girondalones were evaluated:

1.) 1,3,3-Trimethoxy-1-(5-chloro-isothiazoloxyl-3-yl) propane;

2.) 1,3-Dimethoxy-1,3-bis-(5-chloro-isothiazoloxy-3-yl) propane;

3.) 1,3,3-Trimethoxy-1-(isothiazoloxy-3-yl) propane; and

4.) 1,3-Dimethoxy-1,3-bis-(isothiazoloxy-3-yl) propane

                  TABLE 1                                                          ______________________________________                                         Microorganisms used in the Antimicrobial Test                                  Name                Abbreviations Used                                         ______________________________________                                         Bacteria                                                                       Pseudomonas aeruginosa                                                                             Psae                                                       Escherichia coli    Ecol                                                       Staphlococcus aureus                                                                               Saur                                                       Fungi                                                                          Aspergillus niger   Anig                                                       ______________________________________                                    

                  TABLE 2                                                          ______________________________________                                         MIC Values (um)                                                                Psae          Ecol      Saur          Anig                                     Compound                                                                               M9G    TSB    M9G  TSB  TSB     TSB   TSB                              ______________________________________                                         1       0.11   0.22   0.01 0.06 <.0.001  0.011                                                                               0.01                             2       0.08   0.16   0.04 0.08 <0.001  0.01  0.02                             3       0.50   0.25   0.13 0.13 0.06    0.06  0.50                             4       0.37   0.05   0.10 0.19 0.01    0.02  0.75                             ______________________________________                                    

                  TABLE 3                                                          ______________________________________                                         MINIMUM INHIBITORY CONCENTRATION (μm)                                                Pseudomonas  Staphylococcus                                                    aeruginosa   aureus                                                            pH                                                                    Compound   5      7        8.5  5    7      8.5                                ______________________________________                                          ##STR8##  0.06   0.24     0.47 0.03 0.24   0.92                               1          0.23   0.44     0.44 0.11 0.23   0.44                               2          0.08   0.31     0.31 0.02 0.16   0.31                               ______________________________________                                    

                  TABLE 4                                                          ______________________________________                                         MINIMUM INHIBITORY CONCENTRATION (μm)                                              Pseudomonas aeruginosa                                                                        Staphylococcus aureus                                           pH                                                                      Compound 5      7        8.5    5    7      8.5                                ______________________________________                                          ##STR9##                                                                               0.32   0.32     1.24   2.48 2.48   2.48                               3        1.00   2.01     2.01   0.13 0.50   1.00                               4        1.50   >1.50    >1.50  0.19 0.37   0.10                               ______________________________________                                    

Although specific embodiments and examples have been described herein, it should be born in mind that these have been provided by way of explanation and illustration and that the present invention is not limited thereby. Modifications which are within the ordinary skill in the art to make are considered to lie within the scope of the invention as defined by the following claims, including all equivalents. 

What is claimed is:
 1. Girondalone compounds of the formula I ##STR10## wherein A is a residue of a dialdehyde of the formula

    OHC--A--CHO;

R₁ is independently selected from the group consisting of R₂ and (C₁ -C₁₈)alkyl and; R₂ is ##STR11## wherein (i) X₁ and X₂ can be joined to form a 5 or 6 membered fused carbocyclic ring, said ring being saturated, unsaturated, or aromatic; or(ii) X₁ =Cl, H, methyl, or Br; and X₂ =H, Cl, or Br.
 2. Compound according to claim 1 wherein said aldehyde is selected from the group consisting of glutaraldehyde; malonaldehyde; succinaldehyde; octanedial; 2,2-sulfonyl-bis-acetaldehyde; 2,2-oxy-bis-acetaldehyde; 2,2-alkylphosphine oxide-bis-acetaldehyde; succinic acid-2,3-bis-acetaldehyde; phthaldehyde; homophthalaldehyde; 4-octenedial; 2-cylopentene-1,4-dial; and glyoxal.
 3. Compounds according to claim 1 wherein said compound is selected from the group consisting of 1,3,3-trimethoxy-1-(5-chloro-isothiazoloxy-3-yl) propane; 1,3-dimethoxy-1,3-bis-(5-chloro-isothiazoloxy-3-yl) propane; 1,3,3-trimethoxy-1-(isothiazoloxy-3-yl) propane; and 1,3-dimethoxy-1,3-bis-(isothiazoloxy-3-yl) propane.
 4. Method of controlling undesirable microorganisms comprising introducing a girondalone compound according to claim 1 at, into, or onto a locus subject to attack by said microorganisms. 